Acute kidney injury (AKI) caused either by ischemia reperfusion (IR) or by a nephrotoxin is common in hospitalized patients and is associated with an overall mortality rate of up to 50% in the ICU, Despite the high incidence and high mortality rate, there is no specific treatment and the pathophysiology is incompletely understood. Emerging evidence suggests that an antioxidant and oxidant imbalance (or oxidative stress) leading to cell injury, inflammatory, and immune responses participates in the pathogenesis of AKI. Thus, identifying and understanding the functions and regulation of molecular effectors that regulate oxidative stress in response to ischemic and nephrotoxic insults could lead to novel therapeutic opportunities in AKI. In preliminary studies, we found that mice with genetic disruption of Nrf2 (a b-ZIP transcription factor critical for the induction of several antioxidant and cytoprotective gene expression) are more susceptible to IRI-induced vascular permeability and inflammatory responses, as compared with wild type (Nrf2+/+) mice. Nrf2-deficient (Nrf2-/-) mice were also more susceptible to cisplatin-induced nephrotoxic AKI as compared to wild type controls. Antioxidant supplementation significantly improved renal function and histology in Nrf2-/- mice. Based on these preliminary data, we hypothesize that endogenous Nrf2 confers protection in AKI and augmentation of Nrf2 activity is a potential protective strategy for both ischemic and nephrotoxic AKI. As the translocation of Nrf2 from the cytoplasm to the nucleus is critical for ARE- mediated transcriptional response following stressful stimuli, we propose that perturbation in either specific signaling or factors controlling the Nrf2 expression and activation can result in lower levels of antioxidant enzyme expression, thereby contributing to and/or enhancing suscepitibility to the development of AKI. To test these hypotheses, we propose the following three specific aims: 1) Elucidate molecular mechanisms (upstream signals) that control the activation of Nrf2 in response to ischemia reperfusion, 2) Define the contribution of oxidative stress elicited by infiltrating leukocytes compared to resident kidney cells in the development and/or perpetuation of AKI using gene targeted Nrf2 mice, and 3) Determine whether boosting Nrf2 activation using a pharmacologic and a genetic approach confers protection against AKI. Our overall findings obtained from genetically manipulated mouse models and cell culture studies should yield extremely important insights underlying AKI and could have important implications to identify the effector mechanisms causing susceptibility to AKI. The application is developed in a multidisciplinary team approach combining strengths in transcriptional biology, in vitro and in vivo AKI models, and inflammation.